This chapter is most relevant to Section F8(ii) from the 2017 CICM Primary Syllabus, which expects the exam candidates to be able to "describe the carbon dioxide carriage in blood including ...the chloride shift".
- The chloride shift or "Hamburger effect" describes the movement of chloride into RBCs which occurs when the buffer effects of deoxygenated haemoglobin increase the intracellular bicarbonate concentration, and the bicarbonate is exported from the RBC in exchange for chloride.
- This results in a difference of 2-4 mmol/L of chloride between the arterial and venous blood (and a similar difference in bicarbonate concentration).
- The mechanism of the chloride shift:
- Chloride moves into erythrocytes, and bicarbonate moves out, in venous blood.
- CO2 diffuses into the red cells
- There, it is converted to bicarbonate by carbonic anhydrase
- The Band 3 exchange protein then faciitates the diffusion of bicarbonate out of the cell, and chloride into the cell.
- This whole process happens very rapidly, well within the circulating time
- The reverse events take place in the pulmonary capillaries:
- Bicarbonate diffuses back into the red cell, and chloride diffuses out
- Carbonic anhydrase converts bicarbonate back into carbon dioxide and water
- The chloride shift has signficant effects for the organism:
- It mitigates the change in pH which would otherwise occur in the peripheral circulation due to metabolic byproducts (mainly CO2)
- It increases the CO2-carrying capacity of the venous blood
- It increases the unloading of oxgyen, because of the allosteric modulation of the haemoglobin tetramer by chloride (it stabilises the deoxygenated T-state)
Westen & Prange (2003) give a reasonable overview of the situation, but their article is paywalled. So is the excellent paper by Klocke (1988) which basically goes through all the steps in the chloride shift process in excellent detail. Surely if you are going to be throwing money around you may as well buy the official exam textbook. Unfortunately, Hartog Jacob Hamburger's original paper on "Anionenwanderungen in Serum und Blut" is not available, but perhaps that is for our own good.
Westen & Prange (2003) define the chloride shift as:
"the movement of chloride ions from the plasma into red blood cells as blood undergoes the transition from arterial to venous gas partial pressures"
There is probably something more official out there, but most authors give a description which is so close to the one above that it would be meaningless to repeat them all. In short, if this ever comes up in a viva of some sort, so long as one uses the words "chloride" and "erythrocytes" in the same sentence, one should be close to half marks already. The most important points are:
The molecular mechanisms for the chloride shift are described in detail below. In summary, this phenomenon is only possible because of the presence of carbonic anhydrase in RBCs. It is seen as a critically important element (as it is concentrated there, but essentially absent from the bloodstream otherwise). Without it, the reaction converting CO2 to HCO3- would be painfully slow. With massive amounts of erythcyte carbonic anhydrase, we can instead count on these molecular transactions to be complete in the space of one circulatory time. In fact, because all the required proteins are available in massive concentrations, the reaction is incredibly fast. Wieth & Brahm (1980) had determined that 99% of the chloride shift process is complete within about 700 milliseconds.
This whole thing could probably be represented better with some cartoony pictures.
Yes, those potato-looking things are erythrocytes. The numbers came from Western & Prange (2003), whose experiments are discussed below.
At this stage it is important to point out that the movements of chloride are a passive process. Deranged Physiology owes a debt of gratitude to Niels Fogh-Andersen, whose work has informed the understanding of this process, and whose comments have improved the quality of this chapter. In short, Band 3 is not an active transporter, in the sense that it uses no ATP, but a facilitated transport carrier that mediates a passive shift of chloride in (and bicarbonate out) of the erythrocyte, a process that requires no additional energy investment. The main driving forces for the action of this protein are the familiar electrochemical equilibria of chloride and bicarbonate, which are the main ions to which the erythrocyte membrane is permeable (thanks to Band 3). In fact theoretically this system could work without Band 3, and passive diffusion was originally thought to be behind the chloride shift, but (as some early investigators pointed out) in that scenario the diffusion and equilibration of the chloride and bicarbonate would be painfully slow, as the permeability coefficient of the cell membrane to these ions is very low. All this is explained in much more professional language by Hamasaki (1999).
With all this talk of shifting, how much chloride actually shifts? This effect is not exactly seismic. For instance, after determining what electrolyte movements should occur using quantitative physicochemical analysis, Western & Prange (2003) drained blood from healthy volunteers and subjected it to "venous-ification" by exposure to a hypoxic and hypercapnic atmosphere. At a simulated venous gas concentration, the average chloride shift of the samples was approximately 2.4 mmol/L. With a higher haematocrit, closer to 0.55 (they cheated by centrifuge but there really are people out there with such haematocrit values) the investigators were able to measure a chloride shift of around 4.3 mmol/L.
Why is this phenomenon important? Well:
Westen, Edward A., and Henry D. Prange. "A reexamination of the mechanisms underlying the arteriovenous chloride shift." Physiological and Biochemical Zoology 76.5 (2003): 603-614.
Klocke, Robert A. "Velocity of CO2 exchange in blood." Annual review of physiology 50.1 (1988): 625-637.
Hamburger, H. J. "Anionenwanderungen in Serum und Blut unter dem Einfluss von CO2, Säure und Alkali." Biochem Z 86 (1918): 309-324.
Fairbanks, G., Theodore L. Steck, and D. F. H. Wallach. "Electrophoretic analysis of the major polypeptides of the human erythrocyte membrane." Biochemistry 10.13 (1971): 2606-2617.
Wieth, J. O., and J. Brahm. "Kinetics of bicarbonate exchange in human red cells—physiological implications." Membrane transport in erythrocytes. Munksgaard, Copenhagen (1980): 467-487.
Brix, Ole, et al. "The chloride shift may facilitate oxygen loading and unloading to/from the hemoglobin from the brown bear (Ursus arctos L.)." Comparative biochemistry and physiology. B, Comparative biochemistry 95.4 (1990): 865-868.
Fogh-Andersen, N., and Ole Siggaard-Andersen. "Acid-base-induced changes in the distribution of water between plasma and erythrocytes, as measured with a sodium-ion-selective electrode." Clinical chemistry 30.11 (1984): 1843-1845.
Reithmeier, Reinhart AF, et al. "Band 3, the human red cell chloride/bicarbonate anion exchanger (AE1, SLC4A1), in a structural context." Biochimica et biophysica acta (BBA)-Biomembranes 1858.7 (2016): 1507-1532.
Hamasaki, Naotaka. "The role of band 3 protein in oxygen delivery by red blood cells." Indian Journal of Clinical Biochemistry 14.1 (1999): 49-58.